Partial agonists are agents that produce a smaller cellular and behavioral response than a full agonist while occupying the same number of receptors. These agents can potentially "buffer" the effects of either low or high concentrations of full agonist by acting as agonists in the presence of low concentrations of full agonist (increasing total receptor occupancy and net cellular response), and by acting as antagonists in the presence of high concentrations of full agonist (reducing total receptor occupancy and net cellular response). The "biological buffering capacity" of partial dopamine (DA) agonists may allow these agents to serve as therapy for schizophrenia in which positive symptoms (hallucinations, delusions) are postulated to occur due to a dopamine excess in the subcortical limbic system, while negative symptoms (blunted or inappropriate affect) are postulated to occur due to a dopamine deficiency in the prefrontal cortical limbic system. Here, partial agonists could treat negative symptoms by increasing activity of an interactive DA system. Partial agonists could also treat positive symptoms by displacing excess DA from binding sites, leading to a net reduction in cellular response. Drug therapy for schizophrenia has focused on D2 DA receptors, and, more recently, on 5HT2 serotonin receptors. Typical antipsychotics such as haloperidol, which treat positive symptoms of schizophrenia, block D2 receptors competitively, and produce motor side effects. The atypical antipsychotic, clozapine, effective in treating both positive and negative symptoms, can be classified according to D1, D2, and 5HT2 binding affinity (5HT2moreD2 greater than or lesser to D1), and does not produce the extrapyramidal syndrome seen with typical neuroleptics. However, clozapine can produce other serious side effects, including agranulocytosis. Partial DA agonists have the potential to act as antipsychotic agents and produce fewer motor side effects than typical agents, due to mild stimulation of DA receptors in the basal ganglia. Thus, characterization of partial DA agonists at D2 and 5HT receptors may yield alternative strategies for antipsychotic drug therapy. In the proposed experiments, clozapine and drugs known to be D2 DA receptor partial agonists with clinical efficacy in treating schizophrenia will be compared for their relative intrinsic efficacies at recombinant D2A dopamine and 5HT2A serotonin receptors stably expressed in clonal cell lines. Inhibition of forskolin-stimulated cAMP accumulation and 3H-inositol phosphate accumulation, respectively, will be the second messenger responses examined. A novel dose-additive experimental design and data analysis protocol will be employed which quantitatively assesses the enhanced second messenger response to low concentrations of transmitter in the presence of a fixed concentration of partial agonist and the reduced second messenger response to high concentrations of transmitter in the presence of the same fixed partial agonist concentration. This approach operationalizes the concept of biological buffering capacity of potential antipsychotics, evaluates for the first time a dose/additive model for full agonist - partial agonist interactions at recombinant receptors coupled to adenylate cyclase and phospholipase C, and may provide a novel mechanistic basis for the clinical effectiveness of currently used antipsychotics.